Granzymes are a highly conserved group of serine proteases, with five members (A, B, H, K and M) in humans and ten members (A-G, K, M-N) in mice (Sattar R. et al. Biochem Biophys Res Commun 308, 726-35 (2003). Granzyme B (GrB) or cytotoxic T-lymphocyte (CTL)-associated gene transcript-1—Brunet J F. et al. Nature 322, 268-71 (1986)), has been reported as being involved in anti-viral and anti-tumour functions, and is associated with autoimmunity, transplant rejection, graft-versus-host disease, and thymocyte development (Barry M. & Bleackley R C. Nat Rev Immunol 2, 401-9 (2002)).
GrB is reported to have a contribution to CTL-mediated target cell apoptosis. GrB-deficient mice possess a normal phenotype, with the exception of a slightly reduced CTL-mediated target cell apoptosis, anti-viral responses and tumour cell clearance (Revell P A. et al. J Immunol 174, 2124-31 (2005); and Heusel J W. et al. Cell 76, 977-87 (1994)), suggesting a redundancy in immune mediated cell removal. GrB-deficient recipient mice exhibit reduced allograft vasculopathy (Choy J C. et al. Am J Transplant 5, 494-9 (2005)), and its deficiency in mice leads to increased susceptibility to allergen-induced asthma (Devadas, S. et al. Immunity 25, 237-47 (2006)). Choy J C. et al. reported patients with advanced atherosclerosis and transplant vascular disease showed GrB increases with disease severity, and the occasional SMC in advanced plaques, but extracellular GrB staining was absent in advanced disease, while no GrB was observed in healthy arteries (Mod Pathol 16, 460-70 (2003)). In a later publication Choy et al. associate GrB with apoptosis by mediating proteolysis of extracellular proteins through activated T cells and report that cytotoxic T cells localize to medial SMCs in aortic aneurysms (Arterioscler. Thromb. Vasc. Biol.; 24; 2245-2250, (2004)). Skjelland, et al. teach that plasma levels of GrB are increased in patients with lipid rich carotid plaques (Atherosclerosis, 195:e142-e146 (2007)) Kim et al. show that macrophages express granzyme B in the lesion areas of atherosclerosis and rheumatoid arthritis (Immunology Letters, 111, 57-65, (2007)). GrB has also been reported to be associated to cleave vitronectin, fibronectin, and laminin (Buzza M S. et al. JBC vol. 280(25):23549-23558 (2005)). Furthermore, GrB has been associated with acute coronary syndrome (Tsuru R. et al. Heart 94:305-310 (2008) e-published Jun. 25, 2007). GrB has also been reported on in association with rheumatoid arthritis (Goldbach-Mansky et al. Ann Rheum Dis. 64:715-721 (2005); Kraan et al. Ann Rheum Dis 63:483-488 (2004); Villanueva et al. Arthritis Res Ther 7:R30-R37 (2005); and Thewissen et al. Clinical Immunology 123:209-218 (2007)) in inflammatory lung disease (Tremblay et al. J Immunology 165:3966-3969 (2000)), in Chronic Obstructive Pulmonary Disease (Hodge et al. J. of COPD 3:179-187 (2006), and Sjögren's Syndrome (Rosen et al. Crit Rev Oral Biol Med 15(3):156-164 (2004); and Huang et al. Clin Exp Immun 142:148-154 (2005)). GrB inhibitors are also known (for example WO 03/065987).